We have been interested in how intracellular organisms infect mononuclear phagocytes and what determines their survival in these cells. Our previous work showed that Leishmania promastigotes fix complement to their surface by activating the alternative complement pathway, and that the major class of receptors with which they then interact on the macrophage is the complement receptor type 3 (CR3). We have also shown that the parasite surface protease p63 can modify the form of C3 on the surface of the parasite and in this way change the receptor to which the parasite binds. Finally, we have shown that the mechanism of promastigote binding is crucial to the ultimate intracellular fate of the organism. While we are continuing to work on the promastigote form, we have also begun a major effort to analyze the binding, uptake, and fate of the amastigote. We have already reported that amastigotes are also alternative pathway activators. However, preliminary data suggest that they interact primarily with the complement receptor type 1 (CR1), probably because their p63 lacks the proteolytic activity to convert C3b (the CR1 ligand) to C3bi (the CR3 ligand). Using new assays for the binding and intracellular fate of amastigotes, and a number of new analytic techniques for studying the role of complement in parasite-phagocyte interactions, we are now trying to determine how the difference in receptor class between the promastigote and amastigote forms may relate to the ultimate intracellular fate and virulence of the two forms, and how changes in the physiology of cell receptors in the activated macrophage may explain the ability of cell mediated immunity to limit leishmanial infection in vivo.